Overcoming racial health disparities in lung cancer through innovative mechanism-based therapeutic strategies

总结 开发针对健康差异背后的细胞和分子机制的新型治疗方法， 维克森林浸信会综合癌症中心（WFBCCC）的首要任务。我们的胸腔 肿瘤学家一直在积极使用免疫检查点阻断（ICB）药物治疗肺癌患者， 在非小细胞肺癌（NSCLC）患者中的疗效高达30%。我们发现黑人肺癌患者 对ICB的反应明显好于白色患者，表明黑人患者经历的差异 患者可以用ICB治疗。考虑到ICB随时间的耐药性，我们认为， 通过新型ICB和靶向联合治疗实现。我们初步的单细胞RNA测序 （scRNAseq）研究显示，在淋巴细胞中，更多的浸润性耗尽的CD 8 + T细胞和更少的骨髓和自然杀伤细胞。 黑人与白色患者的NSCLC活检比较。在黑人患者的肿瘤中，耗尽的CD 8 + T细胞 表达高水平的CTLA-4和CD 137（4-1BB），表明ICB可能通过 逆转耗尽的T细胞池以恢复抗肿瘤功能。转录途径分析 scRNAseq数据还将氧化还原和脂质代谢确定为最重要的改变的分子变化。基于这些 研究结果和发表的数据显示，氧化还原和脂质介导的免疫细胞重编程调节，我们 提出两个中心假设：（a）在黑人NSCLC患者中，氧化还原和脂质代谢的独特特征 引起功能失调的免疫细胞生态系统，这些生态系统是健康差异的基础，以及（B）这些可以被利用 通过创新的氧化还原和脂质代谢靶向疗法，进一步改善对ICB的反应。肺癌 是WFBCCC最常见的癌症诊断。在我们癌症中心的病人中，14%是黑人， 我们的癌症健康公平办公室收集的流行病学数据显示，我们地区的黑人患者 肺癌发病率和死亡率分别比黑人高15.1%和15.5%， 我们处于一个独特的位置，可以调查导致差异的分子事件。 黑人肺癌患者的ICB反应，并制定有效的治疗策略，以克服健康问题 差距。我们将通过三个具体目标来实现这些目标：1）生成高分辨率的空间 黑、白色患者肿瘤和肿瘤微环境的单细胞表达谱 2）生成将黑人患者NSCLC中的特定基因组事件与 氧化还原和脂质代谢的重编程; 3）产生临床前数据，证明靶向 线粒体氧化还原和脂质代谢可以重塑肿瘤微环境，改善对肿瘤的反应。 ICB。我们将在人源化小鼠模型中使用NSCLC患者来源的类器官和细胞系来确定 MCL 1抑制剂（AZD 5991或VU 661013）和Devimistat（CPI-613）是否可以重编程肿瘤 微环境，改善对ICB的反应。拟议研究的结果将为未来的研究提供信息 指导和指导潜在的临床试验，旨在减少黑人NSCLC患者的癌症差异。

SUMMARY Development of novel therapeutics targeting cellular and molecular mechanisms underlying health disparities is among the top priorities of Wake Forest Baptist Comprehensive Cancer Center (WFBCCC). Our thoracic oncologists have been actively treating lung cancer patients with immune checkpoint blockade (ICB) drugs with up to 30% efficacy in patients with non-small cell lung cancer (NSCLC). We found that Black lung cancer patients showed significantly better response to ICB than White patients, suggesting that disparities experienced by Black patients could be overcome with ICB. Given ICB-resistance over time, we posit that increased efficacy could be achieved through novel ICB and targeted combination therapies. Our preliminary single-cell RNA sequencing (scRNAseq) studies show more infiltrating exhausted CD8+ T cells and fewer myeloid and natural killer cells in NSCLC biopsies from Black compared to White patients. In tumors from Black patients, exhausted CD8+ T cells expressed high levels of CTLA-4 and CD137(4-1BB), suggesting a possible beneficial response to ICB by reversing the pool of exhausted T cells to restore anti-tumor function. Transcriptional pathway analysis of scRNAseq data also identified redox and lipid metabolism as top altered molecular changes. Based on these findings and published data showing redox- and lipid-mediated regulation of immune cell reprogramming, we propose two central hypotheses: (a) In Black NSCLC patients, unique features of redox and lipid metabolism give rise to dysfunctional immune cell ecosystems that underlie health disparities, and (b) these can be exploited by innovative redox and lipid metabolism-targeting therapeutics to further improve response to ICB. Lung cancer is the most frequent cancer diagnosis at WFBCCC. Among patients seen at our Cancer Center, 14% are Black, and epidemiologic data collected by our Office of Cancer Health Equity show that Black patients in our region have lung cancer incidence and mortality rates 15.1% and 15.5% higher, respectively, than rates among Black patients in the U.S. We are in a unique position to investigate the molecular events that lead to differences in ICB responses by Black lung cancer patients and to develop effective therapeutic strategies to overcome health disparities. We will achieve these goals through three Specific Aims: 1) To generate high-resolution spatial single-cell expression profiles of tumors and the tumor microenvironment in Black and White patients with NSCLC; 2) To generate supporting data linking specific genomic events in NSCLC from Black patients to reprogramming of redox and lipid metabolism; 3) To generate pre-clinical data demonstrating that targeting mitochondrial redox and lipid metabolism can reshape the tumor microenvironment and improve response to ICB. We will use NSCLC patient-derived organoids and cell lines in humanized mouse models to determine whether MCL1 inhibitors (AZD5991 or VU661013) and Devimistat (CPI-613) can reprogram the tumor microenvironment and improve response to ICB. Results from the proposed research will inform future study directions and guide potential clinical trials aimed at reducing cancer disparities in Black NSCLC patients.